Diazomethane (CH2=N=N, also known as azimethylene or diazirine) is a highly reactive gas with a wide range of utility in chemical syntheses. It reacts rapidly with carboxylic acids to form the corresponding methyl esters, generally in high yield, with the evolution of gaseous nitrogen. In like manner diazomethane reacts with phenols, enols and alcohols to form methyl ethers with concomitant release of nitrogen; the rate of reaction depending on the acidity of the substrate. A further example of its use is the formation of carbon to carbon bonds with substrates such as acid chlorides and anhydrides. The so formed diazoketones are themselves useful intermediates. Further examples are its use in cycloaddition reactions with olefins to form cylopropanes and nitrogen heterocycles. Similarly chain extension or ring expansion of ketones and conversion of ketones to epoxides can be readily achieved with diazomethane. Still further examples of its use include formation of viral protease inhibitors. A number of viral protease inhibitors including those used to combat HIV are derived from three-carbon amino acid isosteres. An example of these viral protease inhibitors is Nelfinivir Mesylate (Agouron Laboratories). The crucial three-carbon fragment can be built from a two-carbon functionalized amino acid using diazomethane in a modified Arndt-Eistert reaction. This approach is particularly attractive since reaction with diazomethane does not compromise the chiral integrity of the amino acid.
Diazomethane is a powerful carcinogen, allergen and is highly poisonous. However the principle impediment to its use is that it is highly explosive. While the toxic properties of diazomethane can be obviated by judicious plant design and good manufacturing practice, its sensitivity to explosion places greater restraints on its use. The technical literature for the lab-scale synthesis of diazomethane cautions against the use of ground-glass joints and specifically designed firepolished glassware is recommended. The Aldrich Chemical Company, Inc., Milwaukee, Wis., USA markets a “large-scale” DIAZALD® apparatus capable of generating a solution of up to 300 millimoles of diazomethane in diethyl ether by single batch reaction. See Black, T. H., “The Preparation and Reactions of Diazomethane,” Aldrichimica Acta 16(1) 3-10 (1983).
A “large-scale” preparation is disclosed by Acevedo et al in U.S. Pat. No. 5,459,243, “Apparatus and Processes for the Large Scale Generation and Transfer of Diazomethane,” issued Oct. 17, 1995. The reactions disclosed are performed on the 100 millimole scale and generate dilute solutions of diazomethane in dichloromethane.
A batch process for the production of gaseous diazomethane, “A New Method for the Preparation of Diazomethane” is disclosed by De Boer, T. H. J., and Backer, H. J. See Recueil 73 229-234 (1954). The process comprises introducing a solution of potassium hydroxide in a mixture of Carbitol—water to p-toly sulphonylmethylnitrosamide in anisole. A gentle flow of nitrogen is passed through the apparatus and the liberated gaseous diazomethane is obtained in 48% yield. The paper goes on to disclose that when the diazomethane was absorbed immediately in an excess of benzoic acid in ether, the yield was 63%.
More recently Chemistry in Industry, 21 Feb. 1994, page 122/123, in a follow up letter to a publication in the same journal dated 5 Nov., 1990, cautions against the production of gaseous diazomethane because of the explosive risks. This is consistent with Bernd Eistert—“Synthesis with Diazomethane” which states “Gaseous diazomethane, even on dilution with nitrogen, likewise can undergo explosive decomposition, especially at temperatures of 100° C. or higher”.
Indeed it is because of the explosive nature of gaseous diazomethane that the skilled man has tended towards production and use of diazomethane in dilute solutions.
Aerojet—General Corporation (“Aerojet”) is the only company to date to have published procedures to produce diazomethane on a truly large scale.
A large-scale batch production process for the production of solutions of diazomethane is disclosed by Aerojet in U.S. Pat. No. 5,817,778, “Large Scale Batch Process for Diazomethane,” issued Oct. 6, 1998 and European Patent Publication No. EP 0 916 649 A1, “Large Scale Batch Process for Diazomethane,” published can 19 1999. Preparations of diethyl ether solutions of diazomethane are disclosed on the 50 gram-mole to 25,000 gram-mole scale.
A continuous process for the production of solutions of diazomethane has been disclosed by Aerojet in U.S. Pat. No. 5,854,405, “Continuous Process for Diazomethane from an N-methyl-N-Nitrosamine and from Methylurea through N-Methyl-N-Nitroso Urea,” issued Dec. 24, 1998 and European Patent Publication No. EP 0 916 648 A1, “Continuous Process for Diazomethane,” published can 19 1999. This procedure involves dissolving an N-methyl N-nitroso amine in a mixture of two organic solvents—one of which is at least partially water miscible and dissolves the N-methyl-N-nitrosoamine, and the other is one that is substantially less water-miscible than the first and forms a separate phase with water and dissolves diazomethane. A stream of this solution is combined with a stream of an aqueous inorganic base, the aqueous and organic phases are permitted to settle after a suitable residence time and the phases are separated, the diazomethane being recovered as an organic solution. It is stated that because all the stages of the process can be conducted in the liquid phase, the formation of diazomethane vapor is avoided and the risk of detonation is reduced or eliminated. However, the process isolates the diazomethane in a flammable organic solvent which provides a fire risk.
In view of the versatility of diazomethane and its associated hazards a safe and efficient large-scale continuous process providing good yields and preferably obviating the need for volatile and flammable solvents while maintaining a low overall inventory of diazomethane is desirable.